In November 1999, after receiving the Albert Lasker Basic Medical Research Award, Clay Armstrong, in the interview with Denis Baylor, gave the following answer to a hypothetical question from a skeptic student “Why should I care about ion channels?”:

“I think that ion channels are the most important single class of proteins that exist in the human body or any body for that matter”.  (see the full interview here)

I couldn’t believe my ears when I heard this. “…the most important single class of proteins that exist…”???!!! Isn’t that too strong? That might be a joke. I needed to hear it again and again before I could continue to listen to the interview further.

Armstrong put it so clearly, without giving a choice. He didn’t say “very important”, “crucial”, “critical”, “key” etc. No, “…the most important single class of proteins that exist…”, end of story. What an effective approach against skeptics!

Of course, Armstrong understands well that all the systems of the cell/organism are important, and we cannot do well without any of them, but he also really believes that ion channels hold a special place in our body.

So, let’s figure out why Clay Armstrong thinks that ion channels are so important and why we should care about ion channels.

Let’s start at the cellular level. As Clay Armstrong put it:

“No cell could exist without ion channels”.

Why? The answer to this question is not as evident as it could seem to be. At least for me. And I’m probably not alone. A simple Pubmed search gives us something like this:

Ion channels are important regulators of fundamental cellular processes, including differentiation, proliferation, secretion, apoptosis, migration, adhesion, invasion, excitability etc.

While this message clearly (for scientists) suggests that ion channels are important cellular players, it doesn’t imply that ion channels are critical for cellular existence. But are they? The more in-depth search gives grounds to believe that they really are.

This is how Prof. James Tour explained it to his audience at the Dallas Science and Faith Conference in 2019:

“…cellular membrane has proteins-ionophores that allow certain ions IN – certain ions OUT, to keep the ionic concentration at a certain level for maintenance of that cell. As soon as that ionic concentration gets off, you know what happens? BOOOM!!! The cell explodes… ”

I like this explanation as it is both clear and emotional, so people get the message very well. And this message is: ”Membrane proteins that conduct ions are vitally important for the cell”.

Obviously, Prof. Tour is talking about the osmotic problem here. As you know, all living cells have a lipid plasma membrane surrounding the cytoplasm and in this way separating the cell interior from the extracellular space. The backbone of the plasma membrane is a lipid bilayer. The properties of this lipid bilayer are such that it allows only certain molecules to enter or leave the cell. For example, gases like O2 and CO2, hydrophobic molecules, and to a lower extent water can permeate the bilayer, while charged molecules (i.e., ions), as well as large polar molecules, cannot. Thus, without the specialized ion transport system, cell membranes are impermeable for ions but are permeable for water. And this is the problem – the big osmotic problem leading to cell death. Without controlling the intracellular ion concentrations, any cell will not stand the osmotic stress and will either swell to death or shrink to death, depending on the osmotic gradient. By providing the pathway for ions to enter/exit the cell, ion channels and transporters eliminate this critical osmotic problem and allow for acute volume regulation. So, basically, ion channels and transporters save our cells from osmotic death.

Seriously, no jokes, ion channels are just insanely important things for us. I’ll give you some more examples to show how significant ion channels are.

Ion channels ensure that our hearts beat

The mighty ion channels decide to beat or not to beat. The heartbeat is essentially the rhythmic contraction of a heart muscle, which is controlled by specific electrical impulses, called action potentials. And these action potentials, in turn, are the direct result of ion channel function. Therefore, without ion channels, there are no action potentials and the heart cannot beat. Pathogenic alterations in cardiac sodium, potassium, and calcium channels are responsible for such well-known cardiac pathologies as long QT syndrome, Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia.

Ion channels control our movements

The body positions and movements are controlled by muscles. When you are staying, sitting, walking, running, talking, yawning, blinking with your eyes, you use your muscles. When you move, some of your muscles contract while others relax. As in the case of the heart, muscle contraction/relaxation is critically controlled by electrical impulses, totally dependent on ion channel function. Periodic paralysis, Myasthenia gravis, Epilepsy – these are just a few diseases accompanied by pronounced movement impairments induced by alterations in ion channels.

Ion channels underlie our ability to feel the world

The ability to sense the external environment is essential for our survival. That’s why our organism is equipped with a multitude of sensors allowing us to see and hear, sense the smell and taste, feel the touch and pain as well as enjoy cold beverages on a hot summer day. And, you know what? Ion channels run the show here. Not only are they essential for the transduction of the perceived stimuli to the brain, but in many cases, they constitute the sensors themselves. Here are some examples:

We can see the light

Ion channels/receptors transduce light into electrical signals, which in turn are analyzed by our brain to produce visual sensations. The special role here belongs to cyclic nucleotide-gated (CNG) ion channels, which are responsible for the final step of phototransduction. Mutations in these channels cause retinal diseases manifested themselves in the loss of peripheral vision, night blindness, or even total blindness.

We can hear music

In order to hear, our auditory system has to convert sound waves into electrical signals. And this is done by ion channels in the hair cells of the inner ear. The main role here is attributed to mechanoelectrical (or mechanosensory) transduction (MET) channel with transmembrane channel-like protein (TMC) 1 as its pore-forming component. Mutations in TMC1 have been related to hearing impairments, including deafness.

We can smell the flowers

In response to odors, olfactory neurons generate electrical signals which are then transmitted to the brain. Obviously, these electrical signals are generated due to ion channels, present in the membranes of olfactory neurons. While it is generally accepted that CNG channels play a central role here, some other ion channels were also shown to be important regulators of our ability to sense the smell (e.g. Nav1.7).

We can feel the taste of food

Do you like tasty food? Say thanks to ion channels in taste receptor cells. Several ion channels regulate our ability to sense five basic taste qualities (sour, sweet, salty, bitter and umami). Otopetrin-1 is our principal sour taste receptor, ENaC is responsible for salty taste detection, whereas TRPM5 and CALHM1 are considered to be essential for transduction of bitter, sweet and umami tastes.

We can feel the touch

Our ability to feel the touch depends heavily on mechanosensitive ion channels, which identify and convert mechanical stimuli into electrical signals. The main role here is attributed to Piezo channels, whereas the involvement of TREK, TRAAK and others is less clear.

We can enjoy cold drinks on a hot day

In order to detect temperature changes in the external environment, our body utilizes a set of specialized ion channels – thermoreceptors. These ion channels are directly activated by various physiological temperatures ranging from painful cold (TRPA1), mild coolness (TRPM8), warmth (TRPM2, TRPV3, TRPV4), painful heat (TRPV1, TRPM3, ANO1) to extreme heat (TRPV2).

We can feel pain

Well, for all these privileges (to see, hear, feel, etc.), there is a price to pay. And it is painful. Although some people find pain sensations enjoyable, most of us would rather avoid them, and such behavior is important for our survival. A bunch of ion channels has been implicated in the detection and transduction of pain sensations (Nav, Kir, ASIC, TRP, P2X and others), but one of the most remarkable examples is Nav1.7 channel. Remove this channel from your body and you will become painless. PAINLESS!!! You will not feel physical pain anymore! Physicians call this rare condition Congenital Insensitivity to Pain, and painless people live around us. And this is not science fiction.  

I can go on and on with examples, but I think you’ve already got the idea. It turns out that we are totally dependent on ion channels. Clay Armstrong was right by saying that:

“…Ion channels are involved in every thought, every perception, every movement, every heartbeat.” (Nat Med., 1999) .

This is the ion channels’ world and we simply can’t afford not to care about ion channels.

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See you soon.

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Images from: Freeimages.com/John Hughes; Pexels.com/Ady April, Jan Krnc; Pixabay.com/Free-Photos, PublicDomainPictures; Unsplash.com/Samantha Gades, Hyttalo Souza.